1-Nitrophenylpyrido [2,3-d] pyrimidine-2,4(1H,3H)-diones

ABSTRACT

The compounds of the present invention can be represented by the following formula: ##SPC1## 
     Wherein R is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, unsaturated lower alkyl, substituted unsaturated lower alkyl and aralkyl; X is selected from the group consisting of O and S. 
     The compounds of the present invention possess a high degree of pharmacological activities such as anti-inflammatory, anti-ulcerative, analgetic, antipyretic, antihistaminic and central nervous system depressive activities, and certain of them are useful as new anti-inflammatory agents, analgesics and central nervous system depressants.

DETAILED DESCRIPTION

The present invention relates to the compounds represented by thegeneral formula I: ##SPC2##

wherein R is selected from the group consisting of

1. hydrogen,

2. lower alkyl,

3. lower alkenyl,

4. lower alkynyl,

5. aralkyl,

6. lower alkyl substituted with the group consisting of halogen,hydroxyl, lower alkoxy, lower alkanoyloxy, vinyloxy, lowerhydroxyalkoxy, lower cycloalkyl, carboxyl, lower alkoxycarbonyl,di(lower alkyl)amino and six-membered cyclicamino;

X is selected from the group consisting of O and S.

All of the compounds of the present invention possess at least one ofsuch pharmacological activities as anti-inflammatory, anti-ulcerative,analgetic, antipyretic, antihistaminic and central nervous systemdepressive activities as well as low toxicity, and most of them possessmore than one of the said activities. It is to be noted, therefore, thatcertain of the compounds within the scope of the present invention areuseful as new analgesics, anti-inflammatory agents and central nervoussystem depressants.

More particularly, the compounds of the present invention can berepresented by the general formula II: ##SPC3##

wherein R is selected from the group consisting of hydrogen, lower alkylgroups having from one to 6 carbon atoms, lower alkenyl groups havingfrom 3 to 5 carbon atoms, haloallyl, propargyl, cyclopropylmethyl, lowerhaloalkyl groups having from one to 3 carbon atoms, lower trihaloalkylgroups having from one to 3 carbon atoms, acetoxyethyl, lowerhydroxyalkyl groups having from 2 to 3 carbon atoms, lower alkoxyalkylgroups having from 2 to 4 carbon atoms, vinyloxyethyl,hydroxyethoxyethyl, carboxymethyl, ethoxycarbonylmethyl,2,3-epoxypropyl, diethylaminoethyl, 4-methylpiperazinoethyl, benzyl,phenethyl and cinnamyl; X is selected from the group consisting of O andS.

The compounds of the present invention can be prepared in high yields byone of six basic routes as will be described hereinafter.

PREPARATION SERIES I ##SPC4##

wherein R¹ is selected from the group consisting of lower alkyl,substituted lower alkyl, unsaturated lower alkyl and aralky; Y isselected from the group consisting of halogen, arylsulfonyloxy andinorganic acid ester rest. Examples of compounds of the general formula(2) include ethyl iodide, propargyl bromide, 2,2,2-trifluoroethylp-toluenesulfonate, trimethyl phosphate and methyl fluorosulfate.##SPC5##

Wherein R¹ has the same meanings as above; Y is selected from the groupconsisting of carbonyl (--CO--), sulfonyl (--SO₂ --) and oxalyl(--CO--CO--). Examples of compounds of the general formula (4) includedimethyl sulfate, diethyl sulfate, diethyl carbonate and diethyloxalate. ##SPC6##

wherein R² is selected from the group consisting of hydrogen and loweralkyl; Y is selected from the group consisting of oxo (--O--),carbonyldioxo (--O--CO--O--) and sulfinyldioxo (--O--SO--O--). Examplesof compounds of the general formula (5) include ethylene oxide, glycolsulfide, propylene oxide and ethylene carbonate.

The starting materials represented by the general formula (1) may bereacted with the said reagents of the general formulas (2), (4) and (5).

These reactions are preferably carried out in an organic solvent such astoluene, xylene, tetrahydrofuran, dioxane or dimethylformamide. Thereactions as shown in the schemes [I] and [II] should preferably beprocessed in the presence of a metallic compound such as sodiumalcoholate, sodium amide or sodium hydride, or an inroganic salt such asalkali hydroxide or carbonate. The employment of the said metalliccompounds is particularly advantageous in order to obtain the highestyield of the object product.

The desirable temperature is not critical but may be ambient or elevatedtemperature. Since the reaction proceeds very rapidly, room temperatureis sufficient for the reaction and heating is not necessary. The periodof reaction may range from 30 minutes to 3 hours, and may be shortenedby applying mild heating. On the other hand, when oxalic acid diestersand dialkyl carbonates are employed as N-alkylation agent in thereaction scheme [II], the reaction should preferably be performed in anautoclave at a temperature of 150°-240°C.

The reaction solvent is distilled off from the reaction mixture and theresidue is mixed with water to precipitate the crystals of the desiredproduct. Then the obtained crystals may be easily recrystallized frommethanol or a similar solvent for purification.

In the reaction scheme [III], the reaction proceeds in a basic solventat room temperature, but the reaction is finished in a short time whenheated.

PREPARATION SERIES II ##SPC7##

wherein R³ is selected from the group consisting of hydrogen, loweralkyl, substituted lower alkyl and unsaturated lower alkyl; X isselected from the group consisting of O and S; Y and Z are the same ordissimilar and each may be halogen, lower alkoxy, trihalomethyl, aminoor imidazolyl. Examples of compounds of the general formula (8) includeurea, methylurea, diethylurea, N-propylurethane, trichloroacetylchloride, N-ethoxycarbonylimidazole, 1,1'-carbonyldiimidazole, phosgene,ethyl chlorocarbonate, diethyl carbonate, 1,1'-thiocarbonyldiimidazoleand thiophosgene. ##SPC8##

wherein R³ and X have the same meanings as above; R⁴ is lower alkyl.Examples of compounds of the general formula (11) include ethylisocyanate, isopropyl isocyanate and methyl isothiocyanate.

The reactions of these schemes [IV] and [V] proceed smoothly undersimilar conditions preferably in an organic solvent such asdimethylformamide, diglyme, tetrahydrofuran or alcohol, but are mostpreferably performed in the presence of a metallic compound such asmetallic sodium, sodium amide and sodium hydride, or an organic basesuch as trialkylamine and pyridine, or an inorganic base such as alkalihydroxide and carbonate. The first-mentioned metallic compounds are mosteffective to enhance the yield of product. The desirable temperature isnot critical, and may be ambient or elevated temperature. However, thereactions are carried out under ice-cooling when phosgene orthiophosgene is used as a reagent. The reaction solvent is distilled offfrom the reaction mixture under reduced pressure and the residueobtained is mixed with water to precipitate a crude product.Recrystallization of this product from an organic solvent such asacetone or methanol yields pure crystals. ##SPC9##

wherein Y is halogen; R³ and X have the same meanings as above.

The reactions represented by the reaction scheme [VI] are preferablycarried out in an organic solvent such as tetrahydrofuran, diglyme,dichloromethane, benzene, toluene, xylene or dimethylformamide. Thesereactions should be processed in the presence of a metallic compoundsuch as sodium hydride, sodium amide or sodium alcoholate. The reactiontemperature is not critical, but the reaction proceeds smoothly near orat the boiling point of the solvent used. The reaction product can bepurified either by recrystallization from an organic solvent such asmethanol, ethanol, ethyl acetate or acetone, or by column chromatographyto yield pure crystals.

COMPOUNDS

The compounds of the present invention can be prepared by one of thoseroutes as illustrated in the Reaction scheme I-VI. Some examples ofthese compounds and their melting points are shown in Table I.

                  Table I                                                         ______________________________________                                        Examples of the compounds obtained by the present invention                   Compound                        Melting point                                 No.     X        R              (°C)                                   ______________________________________                                        1       O     --H               302 - 303                                     2       "     --CH.sub.3        234 - 235                                     3       "     --C.sub.2 H.sub.5 210 - 211                                     4       "     --CH.sub.2 CH.sub.2 CH.sub.3                                                                    184 - 185                                                   CH.sub.3                                                        5       "     --CH∠       217 - 218                                                   CH.sub.3                                                        6       "     --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           146 - 147                                                   CH.sub.3                                                        7       "     --CH.sub.2 CH∠                                                                            199 - 200                                                   CH.sub.3                                                        8       "     --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                  150 - 151                                     9       "     --CH.sub.2 CH=CH.sub.2                                                                          192 - 193                                                   CH.sub.3                                                        10      "     --CH.sub.2 CH=C∠                                                                          178 -  179                                                  CH.sub.3                                                        11      "     --CH.sub.2 CH=CHCl                                                                              217 - 218                                     12      "     --CH.sub.2 C.tbd.CH                                                                             239 - 240                                     13      "     --CH.sub.2        165 - 166                                     14      "     --CH.sub.2 CH.sub.2 Cl                                                                          202 - 203                                     15      "     --CH.sub.2 CH.sub.2 F                                                                           233 - 234                                     16      "     --CH.sub.2 CF.sub.3                                                                             228 - 229                                     17      "     --CH.sub.2 CH.sub.2 CH.sub.2 Cl                                                                 159 - 160                                     18      "     --CH.sub.2 CH.sub.2 OH                                                                          212 - 213                                     19      "     --CH.sub.2 CH.sub.2 CH.sub.2 OH                                                                 173 - 174                                     20      "     --CH.sub.2 CH--CH.sub.2                                                                         201 - 202                                                   ∠                                                                       O                                                               21      "     --CH.sub.2 CH.sub.2 OCOCH.sub.3                                                                 195 - 196                                     22      "     --CH.sub.2 OCH.sub.3                                                                            184 - 186                                     23      "     --CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                            163 - 164                                     24      "     --CH.sub.2 CH.sub.2 OCH=CH.sub.2                                                                182 -  183                                    25      "     --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 OH                                                       176 - 178                                     26      "     --CH.sub.2 COOH   244 - 245                                     27      "     --CH.sub.2 COOC.sub.2 H.sub.5                                                                   200 - 201                                                   C.sub.2 H.sub.5                                                 28      "     --CH.sub.2 CH.sub.2 --N∠                                                                  156 - 158                                                   C.sub.2 H.sub.5   (Hydrochloride)                                                               250 - 253                                     29      "     --CH.sub.2 CH.sub.2 --                                                                          (Hydrochloride)                               30      "     --CH.sub.2        219 - 220                                     31      "     --CH.sub.2 CH.sub.2                                                                             227 - 228                                     32      "     --CH.sub.2 CH=CH  191 - 192                                     33      S     --CH.sub.3        265 - 266                                     34      "     --C.sub.2 H.sub.5 239 - 240                                     35      "     --CH.sub.2 CH.sub.2 CH.sub.3                                                                    190 - 191                                     36      "     --CH.sub.2 CH=CH.sub.2                                                                          248 - 250                                     37      "     --CH.sub.2 C.tbd.CH                                                                             209 - 210                                     38      "     --CH.sub.2        199 - 200                                     39      "     --CH.sub.2 CF.sub.3                                                                             242 - 243                                     40      "     --CH.sub.2        224 - 226                                     ______________________________________                                    

PHARMACOLOGICAL ACTIVITIES

With respect to numerous compounds of the present invention, the acutetoxicity was tested to ensure their safety, and further central nervoussystem depressive, anti-inflammatory and analgetic effects were testedto prove their excellent activities. The results of each test areindicated in Table II. Each test was conducted in the following manner.

1. Acute toxicity

Each test compound suspended in 0.5 % tragacanth-saline solution wasadministered intraperitoneally or orally to dd-strain male mice (16-24g). The lethal dose was estimated from the death of animals 72 hoursafter administration.

2. Anti-inflammatory effect

A group of five Wistar-strain male rats (100-150 g) were orallyadministered with each test compound suspended in 0.5 %tragacanth-saline solution. After 30 minutes 0.5 %-1.0 % carrageeninsuspended in the water for injection was injected subcutaneously to ahind paw. After 3 hours the carrageenin edema was measured by volume andthe inhibition percentage was determined with respect to the results forthe control animals. The inhibition percentages were shown with thenotations as follows:

    less than 15 % : ±                                                                     31-45 % : ++ more than 61 % : ++++                                16-30 % : + 46-60 % : +++                                                 

3. Analgetic effect

Each test compound suspended in 0.5 % tragacanth-saline solution wasorally administered to dd-strain male mice (18-20 g). After one hour0.6% acetic acid solution was intraperitoneally injected in a volume of0.1 ml/10 g. The writhing syndrome was observed for 10 minutes from 30minutes after the injection, and 50 % analgetic effective dose (ED₅₀)and its 95 % confidential limits were calculated byLitchfield-Wilcoxon's method.

4. Central nervous system depressive effect

Each test compound suspended in 0.5 % tragacanth-saline solution wasinjected intraperitoneally to dd-strain male mice (16-24 g). Thedisappearance of righting reflex was observed under noiselesscircumstances. The dose required for the disappearance of rightingreflex is indicated with the following notations:

    more than 1,000 (mg/kg)) : -                                                                   100-30 (mg/kg) : ++                                          1,000-300 (mg/kg) : ±                                                                       30-10 (mg/kg) : +++                                          300-100 (mg/kg) : +                                                                            less than 10 (mg/kg) : ++++                              

                                      Table II                                    __________________________________________________________________________    Anti-inflammatory, Analgetic and Central Nervous System Depressive            Effects, and Acute Toxicity of the Object Compounds of General Formula:                    anti-inflam-                                                                        analgetic                                                                             C N S                                                                              acute                                                      matory                                                                              effect  depres-                                                                            toxicity                                                   effect                                                                              ED.sub.50                                                                             sive (mg/kg)                                       Standard compounds                                                                         dose(mg/kg)                                                                         (95%C.L.)                                                                             effect                                                                (mg/kg)                                                                 50 10              i.p.                                          __________________________________________________________________________                       290                                                        phenylbutazone                                                                             ++ ±                                                                             (113-435)                                                                             ± 300-1000                                                         180                                                        flufenamic acid                                                                            +  ±                                                                             (131-245)                                                                             -    300-1000                                                         i.p. 56.0                                                  aminopyrine  ±                                                                             ±                                                                             (43.0-73.0)                                                                           /    100-300                                       methaqualone /  /  /       +++  300-1000                                      diazepam     +  ±                                                                             /       ++   300-1000                                      Known analogous compounds                                                                  anti-inflam-                                                                        analgetic                                                                             C N S                                                                              acute                                                      matory                                                                              effect  depres-                                                                            toxicity                                                   effect                                                                              ED.sub.50                                                                             sive (mg/kg)                                                    dose(mg/kg)                                                                         (95%C.L.)                                                                             effect                                                                (mg/kg)                                                    __________________________________________________________________________    R.sup.1                                                                               R.sup.2                                                                             100 50  20 10            i.p. p.o.                              __________________________________________________________________________                                10.0                                                    --C.sub.2 H.sub.5                                                                     ++++                                                                              ++++                                                                              +++                                                                              +++                                                                              (2.0-51.4)                                                                            +++                                                                              600  665                                                           7.1                                                     --CH.sub.3                                                                            +++ +++ +++                                                                              ++ (2.7-18.5)                                                                            ±                                                                             >1000                                                                              >1000                                                         20.0                                                    --CH.sub.2 CH.sub.2 CH.sub.3                                                          ++++                                                                              +++ ++ +++                                                                              (2.9-137.0)                                                                           ±                                                                             >1000                                                                              /                                 __________________________________________________________________________    Object compounds                                                                             anti-inflam-                                                                         analgetic                                                                            C N S                                                                              acute                                                      matory effect depres-                                                                            toxicity                                                   effect ED.sub.50                                                                            sive (mg/kg)                                                    dose(mg/kg)                                                                          (95%C.L.)                                                                            effect                                                                 (mg/kg)                                                 __________________________________________________________________________    X   R        100 50  20  10               i.p. p.o.                           __________________________________________________________________________                                 0.175        200- 1000-                          O --CH.sub.3 ++++                                                                              ++++                                                                              +++ +++ (0.07-0.42)                                                                            +   300  2000                                                        0.113        300- 1000-                          " --C.sub.2 H.sub.5                                                                        /   ++++                                                                              ++++                                                                              ++++                                                                              (0.027-0.476)                                                                          +   1000 2000                                                        2.6                                              " --CH.sub.2 CH.sub.2 CH.sub.3                                                             +++ ++  +++ +++ (1.05-6.40)                                                                            -   1000 >2000                            CH.sub.3                   2.15                                             " --CH∠                                                                              ++++                                                                              +++ +++ +++ (0.93-4.97)                                                                            ++  >1000                                                                              /                                CH.sub.3                                                                      CH.sub.3                   3.1                                              " --CH.sub.2 CH∠                                                                     ++  ++  ++  /   (1.20-8.30)                                                                            ±                                                                              1000 >2000                            CH.sub.3                                                                                                 0.12              200--"                                                                             --CH.sub.2 ++++ ++++ +                                                        +++ ++++ (0.048-0.298)                                                        1++++ 300 500                                          2.6          300-                                " --CH.sub.2 CH=CH.sub.2                                                                   ++++                                                                              ++++                                                                              +++ ++++                                                                              (1.05-6.40)                                                                            ++  1000 >2000                            CH.sub.3                   0.43         200-                                " --CH.sub.2 CH=C∠                                                                   +++ ++++                                                                              ++  ++  (0.18-1.02)                                                                            -   500  >2000                            CH.sub.3                                                                                                 1.15                                             " --CH.sub.2 C.tbd.CH                                                                      ++++                                                                              +++ +++ +++ (0.43-3.09)                                                                            ±                                                                              >1000                                                                              >2000                                                       0.19                                             " -- CH.sub.2 CH.sub.2 Cl                                                                  ++++                                                                              +++ ++++                                                                              +++ (0.09-0.41)                                                                            -   >1000                                                                              >2000                                                                    100-                                " --CH.sub.2 CH.sub.2 F                                                                    +++ ++++                                                                              +++ ++++                                                                              ≈0.01                                                                          ++  300  2000                                                        1.28                                             " --CH.sub.2 CF.sub.3                                                                      +++ +++ ++++                                                                              +++ (0.53-3.10)                                                                            +   >1000                                                                              >2000                                                       0.42                                             " --CH.sub.2 CH.sub.2 OH                                                                   ++  ++  /   /   (0.15-1.15)                                                                            ±                                                                              >1000                                                                              >2000                          " --CH.sub.2 CH.sub.2 CH.sub.2 OH                                                          ++++                                                                              +++ +++ ++  ≈ 1.0                                                                          ±                                                                              >1000                                                                              >2000                                                       0.16                                             " --CH.sub.2 CH.sub.2 OCOCH.sub.3                                                          ++  +   /   /   (0.06-0.43)                                                                            -   >1000                                                                              2000                                                        0.168                                            O --CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                     ++  +++ +++ ++  (0.06-0.44)                                                                            ++  >1000                                                                              /                                                           33.0                                             " --CH.sub.2 COOH                                                                          /   ++  +   /   (13.5-80.9)                                                                            +   >1000                                                                              >2000                                                       45.0                                             " --CH.sub.2 COOC.sub.2 H.sub.5                                                            +++ +++ ++  ++  (17.3-117)                                                                             ±                                                                              1000 >2000                                                       1.7                                              " --Ch.sub.2 ++++                                                                              +++ +++ ++  (0.63-4.56)                                                                            -   1000 2000                           " --CH.sub.2 CH.sub.2                                                                      ±                                                                              -   -   /   >100     +   >1000                                                                              >2000                          " --CH.sub.2 CO                                                                            ±                                                                              /   /   /   >100     -   >1000                                                                              >2000                          S --CH.sub.3 /   + ++                                                                              /   +++ (0.23-1.55)                                                                            -   >1000                                                                              >2000                          " --C.sub.2 H.sub.5                                                                        /   +++ /   +++ ≈ 0.2                                                                          ++  >1000                                                                              >2000                          " --CH.sub.2 CH.sub.2 CH.sub.3                                                             /   +   /   +   ≈ 1000                                                                         -   >1000                                                                              >2000                                                       0.23                                             " --CH.sub.2 CF.sub.3                                                                      /   +++ /   ++++                                                                              (0.07-0.77)/ ±                                                                      >1000                                                                             >2000                               __________________________________________________________________________

The present invention is illustrated hereinafter, but not limited tothese Examples.

EXAMPLE 1

2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione wasdissolved in 30 ml of dry dimethylformamide. To the solution was added0.6 g of approximately 50 % sodium hydride and stirring was performedfor 30 minutes. To this was added 3.4 g of allyl iodide and the mixturewas reacted for 3 hours at room temperature. Then the solvent wasevaporated from the mixture under reduced pressure. To the residueobtained was added water to precipitate a crude product.Recrystallization of this product from methanol gave 2.3 g of1-(m-nitrophenyl)-3-allylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione aspale yellow prisms, melting at 188-189°C.

Analysis--Calculated for C₁₆ H₁₂ N₄ O₄ : C, 59.26 ; H, 3.73 ; N, 17.28.Found: C, 59.12; H, 3.87; N, 17.31.

EXAMPLE 2

To a solution of1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and 30 ml ofdry dimethlformamide was dimethylformamide 0.6 g of about 50 % sodiumhydride, and stirring was performed for 30 minutes. To this was addeddropwise 2.3 g of methyl fluorosulfate and the mixture was reacted forone hour at room temperature. Then the mixture was neutralized with 5 %sodium carbonate solution and concentrated under reduced pressure toleave a residue, to which was added water to yield a crude product. Thisproducts was recrystallized from acetone to give 2.6 g of1-(m-nitrophenyl)-3-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione aspale yellow prisms, melting at 234°-235°C.

Analysis--Calculated for C₁₄ H₁₀ O₄ N₄ : C, 59.63; H, 3.13 N, 17.39.Found: C, 59.52; H, 3.21; N, 17.21.

EXAMPLE 3

2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione wasdissolved in 30 ml of dry dimethylformamide. To this was added 4.2 g oftrimethyl phosphate and the mixture was refluxed for 6 hours. After thereaction was complete, the solvent was distilled off from the mixture,and to the residue obtained was added water to precipitate a crudeproduct. The product was recrystallized from acetone to yield 2.5 g of1-(m-nitrophenyl)-3-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione aspale yellow prisms, melting at 234°-235°C.

EXAMPLE 4

To a mixture of 2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and 30 ml of dry dimethylformamide was added 0.6 g ofapproximately 50 % sodium hydride. The mixture was stirred for 30minutes at room temperature and for additional 10 minutes at atemperature of 70°-80°C. To the mixture was further added dropwise 3.4 gof benzyl bromide and stirring was continued for 30 minutes. The solventwas removed from the resulting mixture by distillation, and to theresidue was added water to give a crude precipitate. This product wasrecrystallized from a mixture of methanol and dimethylformamide to yield3.3 g of1-(m-nitrophenyl)-3-benzylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione aspale yellow prisms, melting at 219°-220°C.

Analysis--Calculated for C₂₀ H₁₄ N₄ O₄ : C, 64.17; H, 3,77; N, 14.97.Found: C, 64.03; H, 3.84; N, 14.82.

EXAMPLE 5

2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione wasdissolved in 30 ml of dry dimethylformamide. To the solution was added0.6 g of about 50 % sodium hydride, and stirring was performed for 30minutes. To the mixture was further added 3.5 g of diethylsulfite andthe whole was reacted for 2 hours at room temperature. After thereaction was finished, the solvent was distilled off from the mixtureunder reduced pressure. To the residue thus obtained was added water toprecipitate a crude product. This product was recrystallized frommethanol to yield 2.7 g of1-(m-nitrophenyl)-3-ethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione aspale yellow prisms, melting at 210°-211°C.

Analysis--Calculated for C₁₅ H₁₂ N₄ O₄ : C, 57.69; H, 3.87; N, 17.94.Found: C, 57.52 H, 3,81; N, 17.93.

EXAMPLE 6

2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione wasdissolved in 30 ml of dimethylformamide. To the solution was added 0.6 gof about 50 % sodium hydride and the whole was stirred for 20 minutes atroom temperature, and then heated up to 90°C. To this was added dropwisea solution of 7.5 g of 2,2,2-trifluoroethyl p-toluenesulfonate and 20 mlof tetrahydrofuran and the mixture was reacted for 2 hours. After thereaction was complete, the solvent was removed from the resultingmixture by distillation, and to the residue obtained was added water toprecipitate a crude product. This product was recrystallized frommethanol to yield 3.2 g of1-(m-nitrophenyl)-3-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneas pale yellow prisms, melting at 228-229°C.

Analysis--Calculated for C₁₄ H₉ F₃ N₄ O₄ : C, 49.19; H, 2.48; N, 15.30,Found: C, 49.00; H, 2.49; N, 15.21.

EXAMPLE 7

To a solution of 2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and 30 ml of dimethylformamide was added 0.53 g of 55 %sodium hydride, and the solution was heated up to 150°C. To this wasadded 0.97 g of ethylene carbonate, and the mixture was reacted for onehour at 150°C. After the reaction was complete, the solvent wasdistilled off from the resulting mixture under reduced pressure. To theresidue obtained was added water to precipitate a crude product. Thisproduct was recrystallized from methanol to yield 2.8 g of1-(m-nitrophenyl)-3-(2-hydroxyethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at212°-213°C.

Analysis--Calculated for C₁₅ H₁₂ N₄ O₅ : C, 54.88; H, 3.68; N, 17.07.Found: C, 54.93; ; H, 3.65; N, 17.16.

EXAMPLE 8

To a solution of 3.0 g of 2-(m-nitroanilino)niotinic acid allylamide and25 ml of dry tetrahydrofuran was added 1.0 g of approximately 55 %sodium hydride, and the whole was stirred for 30 minutes. To this wasadded dropwise 4.2 g of 1-ethoxycarbonylimidazole, and the mixture wasrefluxed for 3 hours. After the reaction was complete, the solvent wasdistilled off from the reaction mixture to leave a residue, to which wasadded water to precipitate a crude product. This product wasrecrystallized from methanol to yield 3.0 g of1-(m-nitrophenyl)-3-allylpyrido[2,3-d] pyrimidine-2,4(1H,3H)-dione aspale yellow prisms, melting at 188°-189°C.

Analysis-Calculated for C₁₆ H₁₂ N₄ O₄ : C, 59.26; H, 3.73; N, 17.28.Found: C, 59.03; H, 3.82; N, 17.43.

EXAMPLE 9

To a solution of 1.25 g of 2-(m-nitroanilino)nicotinic acid methylamideand 20 ml of tetrahydrofuran was added 0.48 g of approximately 50 %sodium hydride and the mixture was stirred for 30 minutes. To themixture was further added dropwise 2.3 g of thiophosgene under coolingwith ice and the resultant mixture was allowed to stand for 30 minutesat room temperature. An excess of thiophosgene was decomposed withadding methanol-ammonia solution. The solvent was distilled off from themixture to give a residue, to which was added water to precipitate acrude product. Recrystallization of this product from acetone gave 1.2 gof1-(m-nitrophenyl)-3-methyl-2-thio-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidineas pale yellow prisms, melting at 265°-266°C.

Analysis--Calculated for C₁₄ H₁₀ N₄ O₃ S : C, 53.51; H, 3.21; N, 17.83.Found: C, 53.63; H, 3.19; N, 17.69.

EXAMPLE 10

To a solution of 1.9 g of 2-chloronicotinic acid propargylamide and 20ml of dry dimethylformamide was added 1.0 g of 50 % sodium hydride, andthe solution was stirred for 30 minutes. To this was further added 2.3 gof m-nitrophenylisothiocyanate and the mixture was refluxed for 6 hours.After the reaction was complete, the mixture was concentrated underreduced pressure to removed the solvent. The concentrate was passedthrough a column of silica gel and the adsorbate was eluted with ethylacetate. The crystals thus obtained were further purified byrecrystallization from methanol to yield 2.3 g of1-(m-nitrophenyl)-3-propargyl-2-thio-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidineas pale yellow prisms, melting at 209°-210°C.

Analysis--Calculated for C₁₆ H₁₀ N₄ O₃ S : C, 55.80; H, 4.68; N, 16.27.Found: C, 55.77; H, 4.65; N, 16.31.

EXAMPLE 11

To a solution of 5.7 g of 2-(m-nitroanilino)nicotinic acid ethyl esterand 50 ml of dry tetrahydrofuran was added 1.1 g of sodium amide and thesolution was stirred for one hour. To this was added dropwise undercooling 2.9 g of ethyl isocyanate and this mixture was reacted at 60°Cfor 10 hours. After the reaction was complete, the solvent was distilledoff from the mixture, and to the residue obtained was added water toprecipitate a crude product. This product was collected by filtrationand recrystallized from methanol to give 3.4 g of1-(m-nitrophenyl)-3-ethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ascolorless needles, melting at 210°-211°C.

What is claimed is:
 1. A compound of the formula: ##SPC10##wherein R isselected from the group consisting of hydrogen, lower alkyl having fromone to 6 carbon atoms, lower alkenyl having from 3 to 5 carbon atoms,propargyl, cyclopropylmethyl, lower haloalkyl having from one to 3carbon atoms, lower trihaloalkyl having from one to 3 carbon atoms,vinyloxyethyl, acetoxyethyl, lower hydroxyalkyl having from 2 to 3carbon atoms, lower alkoxyalkyl having from 2 to 4 carbon atoms,haloallyl, hydroxyethoxyethyl, ethoxycarbonylmethyl, carboxymethyl,2,3-epoxypropyl, diethylaminoethyl, 4-methylpiperazinoethyl, benzyl,phenethyl and cinnamyl; x is selected from the group consisting of O andS.
 2. A compounnd in accordance with claim 1 of the formula:##SPC11##wherein R¹ is selected from the group consisting of hydrogen,lower alkyl having from one to 6 carbon atoms, lower alkenyl having from3 to 5 carbon atoms, propargyl, cyclopropylmethyl, lower haloalkylgroups having from one to 3 carbon atoms, lower trihaloalkyl having fromone to 3 carbon atoms, vinyloxyethyl, acetoxyethyl, lower hydroxyalkylhaving from 2 to 3 carbon atoms, lower alkoxyalkyl having from 2 to 4carbon atoms, haloallyl, hydroxyethoxyethyl, ethoxycarbonylmethyl,carboxymethyl, 2,3-epoxypropyl, diethylaminoethyl,4-methylpiperazinoethyl, benzyl, phenethyl and cinnamyl.
 3. A compoundin accordance with claim 1 of the formula: ##SPC12##wherein R² isselected from the group consisting of lower alkyl having from one to 6carbon atoms, allyl, propargyl, cyclopropylmethyl, 2,2,2-trifluoroethyland benzyl.